The present invention relates to pharmaceutical formulations comprising an anti-inflammatory glucocorticoid compound of the androstane series and levocabastine, an H1 antagonist/anti-allergic. The present invention also relates to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions, specifically rhinitis.
Many millions of individuals suffer from seasonal and perennial allergic rhinitis worldwide. Symptoms of seasonal and perennial allergic rhinitis include nasal itch, congestion, runny nose, sneezing and watery eyes. Seasonal allergic rhinitis is commonly known as ‘hay fever’. It is caused by allergens which are present in the air at specific times of the year, for example tree pollen during Spring and Summer. Perennial allergic rhinitis is caused by allergens which are present in the environment during the entire year, for example dust mites, mould, mildew and pet dander.
The majority of allergic rhinitis sufferers report nasal symptoms (congestion, sneezing, itching and rhinorrhea) and ocular symptoms (redness, watery eyes, itching and burning) which impact quality of life and can also be associated with substantial healthcare costs (e.g. exacerbations of sinusitis and asthma, nasal polyps, hearing impairment, etc) and other economic impacts (e.g. less work productivity) if not treated properly.
The goal of allergic rhinitis therapy is to manage both the acute and chronic manifestations of the disease by minimising the associated symptoms and improving quality of life. To achieve this, current treatment recommendations include allergen avoidance, immunotherapy and/or pharmacotherapy. Avoidance is difficult to achieve for the most common allergens (e.g., pollen, dust mites). Immunotherapy is an effective chronic therapy in some patients but it is time-consuming, inconvenient, and has potential serious adverse effects (such as large local reactions and anaphylaxis). Current pharmacotherapy options include intranasal corticosteroids, oral and intranasal antihistamines (AH), non-steroidal anti-inflammatory agents and decongestants.
To formulate an effective pharmaceutical nasal composition, the medicament must be delivered readily to all portions of the nasal cavities (the target tissues) where it performs its pharmacological function. Additionally, the medicament should remain in contact with the target tissues for relatively long periods of time. The longer the medicament remains in contact with the target tissues, the greater the efficacy, and therefore the medicament must be capable of resisting those forces in the nasal passages that function to remove particles from the nose. Such forces, referred to as ‘mucociliary clearance’, are recognised as being extremely effective in removing particles from the nose in a rapid manner, for example, within 10 to 30 minutes from the time the particles enter the nose.
Other desired characteristics of a nasal composition are that it must not contain ingredients which cause the user discomfort, that it has satisfactory stability and shelf-life properties, and that it does not include constituents that are considered to be detrimental to the environment, for example ozone depletors. In the case of administration of glucocorticoids, the potential for any undesirable side effects should preferably be minimised.
Glucocorticoids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis.
Inhaled corticosteroids include beclomethasone esters (e.g. the 17-propionate ester or the 17,21-dipropionate ester), fluticasone propionate, budesonide, flunisolide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, and ciclesonide. Inhaled glucocorticoids are also disclosed in WO02/12265, WO02/12266, WO05/005452, WO05/005451 and WO02/088167.
WO02/12265 discloses 6α,9α-difluoro-17α-[(2-furanylcarbony)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, known by the generic name fluticasone fluroate.
H1 antagonists/antiallergics (also referred to as antihistamines) are known and can be used in nasal sprays and eye drops to treat allergy-related conditions, such as seasonal allergic rhinitis and in the treatment of itching of the eye associated with allergic conjunctivitis. Antihistamines may be referred to as first, second or third generation antihistamines.
First generation H1 antihistamines include piperoxam, ethylenediamines (e.g. mepyramine (pyrilamine), antazoline), ethanolamines (e.g. diphenhydramine, carbinoxamine, doxylamine, clemastine, and dimenhydrinate), alkylamines (e.g. pheniramine, chlorenamine (chlorpheniramine), dexchlorphenamine, brompheniramine, and triprolidine), piperazines (e.g. cyclizine, hydroxyzine, and meclizine), and tricyclics (e.g. promethazine, alimemazine (trimeprazine), cyproheptadine, and azatadine).
Second-generation antihistamines include systemic drugs (e.g. acrivastine, astemizole, cetirizine, loratadine, mizolastine, and terfenadine) and topical drugs (e.g. azelastine, levocabastine, and olopatidine). It is known that levocabastine, usually as the hydrochloride salt, for example as disclosed in U.S. Pat. No. 3,813,384, can be administered as a nasal spray to treat conditions such as rhinitis. Commercially available formulations of levocabastine are typically intended for twice daily administration.
Third generation antihistamines include levocetirizine, desloratidin and fexofenadine.
We have now identified novel formulations comprising a corticosteroid and an H1 receptor antagonist. Said formulations are suitable for intranasal administration and may have advantages over those formulations already known.